Clostridium difficile is an anaerobic pathogenic bacterium that causes infection of the colon typified by severe diarrhea, pseudomembranous colitis, and, in extreme cases, colonic rupture, sepsis and death. The symptoms of C. difficile infection (CDI) are caused by two exotoxins, toxin A (TcdA) and toxin B (TcdB) that are thought to target colonocytes via similar mechanisms involving glucosylation of small GTPases such as Rac and Rho. Inactivation of these important enzymes leads to morphological changes and eventually cell death, disruption of the colonic trans-epithelial resistance and the initiation and propagation of deleterious inflammatory events. Entry of the toxins into cells occurs through binding of the toxins to receptors on the cell surface, internalization via endocytosis, pH-induced conformational changes including formation of a trans-membrane pore that allows for transport and release (via autoproteolytic cleavage) of the glucosylransferase domain of the toxins into the cytoplasm.
Bezlotoxumab is an anti-C. difficile toxin B human monoclonal antibody useful for the treatment and prevention of C. difficile infection. Understanding the nature of the bezlotoxumab interaction with the toxin B is important to the design of further therapeutic antibodies and vaccines for treating C. difficile infection.